Detailed characterization of the antigenetic, biologic and genetic properties of normal human melanocytes, non-malignant nevus cells, and primary and metastatic melanoma cells has provided the basis for a multidisciplinary study of the etiology, biology, immunology, and pathology of melanoma progression and of the therapy of melanoma. The long-term objectives are to search for molecular mechanisms for the development of melanoma that will allow novel approaches in diagnosis and therapy. Human melanoma probably develops in sequential steps as a clonal expansion of genetically altered cells and cells from lesions at different steps of tumor progression have characteristic properties distinguishing each lesional step. The individual projects have common, interrelated themes and will focus on the following critical issues: 1 . The biological analysis of differentiation and transformation pathways for melanocytic cells, the biochemical and molecular characterization of melanocyte- and melanoma-associated antigens, and the mechanisms of growth regulation by growth factors of cells at different steps of tumor progression. 2. The cloning of genes involved in tumor progression and regression and the delineation of novel attributes for prediction of disease outcome. 3. The immunogenicity of tumor-associated antigens in active immunization approaches in experimental animals and immunotherapy of melanoma inpatients with monoclonal antibodies. This program is a collaborative effort at The Wistar Institute, The University of Pennsylvania Cancer Center and The Departments of Pathology and Dermatology at the Hospital of the University of Pennsylvania, and the University of Uppsala.